Effect of L-NAME-induced hypertension on melatonin receptors and melatonin levels in the pineal gland and the peripheral organs of rats

Abstract

Melatonin plays a role in blood pressure (BP) control. The aim of this study was to determine whether melatonin concentrations and melatonin receptor levels are altered in L-NAME-treated, NO-deficient hypertensive rats. Two groups of male adult Wistar rats were investigated: rats (n¼36) treated with NO-synthase inhibitor L-NAME (40 mg kg À1 ) and age-matched controls (n¼36). BP was measured weekly by tail-cuff plethysmography. After 4 weeks, L-NAME administration increased BP (178±1 vs. control 118 ± 1 mm Hg). At the end of treatment, rats were killed in regular 4 h intervals over a 24-h period. Melatonin concentrations in the plasma, pineal gland, heart and kidney and melatonin receptor (MT 1 ) density in the aorta were determined. A significant daily rhythm of melatonin concentrations was found in the blood, pineal gland, kidney and heart of both control and hypertensive rats. Peak nighttime pineal melatonin concentrations were higher in L-NAME-treated rats than in controls (3.38 ± 0.48 vs. 1.75 ± 0.33 ng per pineal gland). No differences between both groups were found in melatonin concentrations in blood, kidney and heart or in the MT 1 receptor density in the aorta. Our results suggest that L-NAME treatment enhances melatonin production in the pineal gland, potentially by decreasing an inhibitory effect of NO on melatonin production in the pineal gland. However, the enhanced pineal melatonin formation was insufficient to increase melatonin concentrations in circulation, heart and kidney of L-NAME-treated rats, indicating an increased use of melatonin in hypertensive animals. INTRODUCTIONMelatonin is a hormone produced by the pineal gland in a circadian manner and exhibits a broad spectrum of effects, including those in the cardiovascular system. Melatonin has been suggested to play a role in blood pressure (BP) control. Earlier reports have shown that pinealectomized rats developed hypertension, 1 and the administration of melatonin in this model normalized the increased BP. 2 Melatonin decreased BP in hypertensive patients, 3 and the addition of melatonin to antihypertensive medication in patients with nocturnal hypertension reduced nighttime systolic BP. 4 However, the mechanisms behind melatonin's effect on BP are still not completely understood.The hypotensive effect of melatonin could be mediated either by a direct effect on vessels or by decreasing brain serotonin release, resulting in sympathetic inhibition or parasympathetic stimulation. 5 There are rather limited data about changes of melatonin concentrations related to essential hypertension in the literature. Plasma melatonin and urinary 6-sulfatoxymelatonin levels have been reported

The Presence and Localization of Melatonin Receptors in the Rat Aorta

“…Expression of MT 1 was additionally confirmed at the protein level by Western blotting. These results extend our previous findings in the rat aorta (Benova et al 2009) and are in line with the MT 1 presence in other blood vessels in rats (Dubocovich and Markowska 2005) and the human aorta (Ekmekcioglu et al 2001). We confirmed the presence of MT 1 mRNA by two different RT-PCR techniques applying two different sets of primers and identified the amplicon by sequencing.…”

“…While the expression of MT 1 protein had been shown (Benova et al 2009), demonstration of mRNA expression failed (Chucharoen et al 2003), and 125 I-MEL binding was not observed (Viswanathan et al 1990). Finally, while MT 2 mRNA expression was shown in human aorta (Ekmekcioglu et al 2003), a study in the rat aorta failed to detect the same (Chucharoen et al 2003).…”

Peripheral and Central Effects of Melatonin on Blood Pressure Regulation

“…MT1 expression was observed in the rat aorta [42,43,44], while these receptors were surprisingly localized mainly in the tunica adventitia and not in the smooth muscle and/or endothelial cells [43], and in rat caudal artery [45]. MT2 were observed in porcine coronary arteries [46], in rat caudal artery [45], but not in the aorta [43].…”

“…However, in the same experiment, in peripheral organs, melatonin levels were not substantially changed. It has been suggested that increased melatonin production was insufficient to counterbalance the augmented melatonin consumption in the peripheral tissues [42]. Similarly, in rats with chronic immobilization stress and increased sympathetic nerve activity and enhanced circulating norepinephrine levels, the nocturnal melatonin levels were increased [127].…”

Elevated heart rate and nondipping heart rate as potential targets for melatonin: a review

“…The data from our laboratory indicate that the melatonin level in the pineal gland was increased in L‐NAME‐hypertensive animals relative to these in control rats. It was suggested that the increased sympathetic tone or reduced NO production in the PVN in L‐NAME‐treated rats might have underlined the potentially compensatory enhancement of melatonin formation . Also, chronic immobilization stress in rats induced an enhancement of circulating norepinephrine levels along with the increase in nocturnal level of melatonin .…”